Emerging data suggest that the development of chronic obstructive lung diseases is greatly influenced (and perhaps pre-determined) by adverse exposures in early life. However, the exact causes and mechanisms responsible for such long-lasting events remain unclear. We explored how early life exposure to tobacco components might promote maladaptions that lead to the development of chronic obstructive lung disease in the adult. We focused on nicotine as this tobacco plant alkaloid readily traverses the placenta and impacts cell functions via activation of nicotinic acetylcholine receptors (nAChRs). In earlier work, we showed that exposure of embryonic murine lung explants to nicotine resulted in aberrant lung branching morphogenesis. Further work revealed that peri-natal nicotine exposure in vivo resulted in abnormal airway structure and function in the young lung characterized by alterations in airway branching and increased ext racellular matrix (ECM) deposition around the airways; these changes were associated with airway hyperreactivity. Notably, these effects were found to be mediated via ?? nAChRs, thereby unveiling potential targets for intervention. More relevant to this proposal, we recently observed that chronic exposure to nicotine starting during embryogenesis promoted lung structural and functional abnormalities detectable later in life (adulthood). Further experiments suggested a link between these changes and aberrant expression of ECM genes via epigenetic mechanisms of action. Finally, we observed that Influenza A infection of the young lung also promoted long-lasting effects, and these amplified the effects of nicotine. These observations led to the hypothesis that exposure to nicotine starting in early life promotes long-standing structural and functional abnormalities in lung through the activation of nAChRs, and via alterations in the expression of ECM genes involved in pre-natal and post-natal lung development through epigenetic mechanisms of action. These effects can be amplified by a second hit (i.e., viral infection early after birth). This hypothesis will be tested in aims designed to: 1) Determine the role of nAChRs in these events using genetic and pharmacological interventions (Aim 1), Examine the nicotine-dependent, gene-specific, promoter-associated epigenetic modifications regulating ECM gene expression in primary lung fibroblasts (Aim 2), and Investigate the impact of a second hit (e.g., early post-natal viral infection) on nicotine-induced changes in the adult mammalian lung (Aim 3).